MMEL1_RAT
ID MMEL1_RAT Reviewed; 774 AA.
AC P0C1T0;
DT 05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-SEP-2006, sequence version 1.
DT 03-AUG-2022, entry version 96.
DE RecName: Full=Membrane metallo-endopeptidase-like 1;
DE EC=3.4.24.11;
DE AltName: Full=NEP2(m);
DE AltName: Full=Neprilysin II;
DE Short=NEPII;
DE AltName: Full=Neprilysin-2;
DE Short=NEP2;
DE Short=NL2;
DE Contains:
DE RecName: Full=Membrane metallo-endopeptidase-like 1, soluble form;
DE AltName: Full=Neprilysin-2 secreted;
DE Short=NEP2(s);
GN Name=Mmel1; Synonyms=Mell1, Nep2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), AND TISSUE SPECIFICITY.
RX PubMed=10814502; DOI=10.1006/bbrc.2000.2664;
RA Ouimet T., Facchinetti P., Rose C., Bonhomme M.-C., Gros C.,
RA Schwartz J.-C.;
RT "Neprilysin II: a putative novel metalloprotease and its isoforms in CNS
RT and testis.";
RL Biochem. Biophys. Res. Commun. 271:565-570(2000).
RN [2]
RP ERRATUM OF PUBMED:10814502.
RA Ouimet T., Facchinetti P., Rose C., Bonhomme M.-C., Gros C.,
RA Schwartz J.-C.;
RL Biochem. Biophys. Res. Commun. 275:247-247(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [4]
RP TISSUE SPECIFICITY.
RX PubMed=12710972; DOI=10.1016/s0306-4522(02)01002-3;
RA Facchinetti P., Rose C., Schwartz J.C., Ouimet T.;
RT "Ontogeny, regional and cellular distribution of the novel metalloprotease
RT neprilysin 2 in the rat: a comparison with neprilysin and endothelin-
RT converting enzyme-1.";
RL Neuroscience 118:627-639(2003).
RN [5]
RP BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF ARG-131; SER-133; ASN-567
RP AND LEU-739.
RX PubMed=15294904; DOI=10.1074/jbc.m407333200;
RA Voisin S., Rognan D., Gros C., Ouimet T.;
RT "A three-dimensional model of the neprilysin 2 active site based on the X-
RT ray structure of neprilysin. Identification of residues involved in
RT substrate hydrolysis and inhibitor binding of neprilysin 2.";
RL J. Biol. Chem. 279:46172-46181(2004).
RN [6]
RP GLYCOSYLATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=11964170; DOI=10.1042/0264-6021:3630697;
RA Rose C., Voisin S., Gros C., Schwartz J.-C., Ouimet T.;
RT "Cell-specific activity of neprilysin 2 isoforms and enzymic specificity
RT compared with neprilysin.";
RL Biochem. J. 363:697-705(2002).
RN [7]
RP MUTAGENESIS OF PRO-751; PRO-764 AND TRP-774.
RX PubMed=16081046; DOI=10.1016/j.bbrc.2005.07.081;
RA Voisin S., Ouimet T.;
RT "The ultimate tryptophan residue of neprilysin 2 is not involved in protein
RT maturation and enzymatic activity.";
RL Biochem. Biophys. Res. Commun. 335:356-360(2005).
CC -!- FUNCTION: Metalloprotease involved in sperm function, possibly by
CC modulating the processes of fertilization and early embryonic
CC development. Degrades a broad variety of small peptides with a
CC preference for peptides shorter than 3 kDa containing neutral bulky
CC aliphatic or aromatic amino acid residues. Shares the same substrate
CC specificity with MME and cleaves peptides at the same amide bond (By
CC similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Preferential cleavage of polypeptides between hydrophobic
CC residues, particularly with Phe or Tyr at P1'.; EC=3.4.24.11;
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250};
CC -!- ACTIVITY REGULATION: Inhibited by thiorphan and phosphoramidon.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=62 uM for Tyrosyl-D-Ala(2)-Leu(5)-enkephalin
CC {ECO:0000269|PubMed:11964170, ECO:0000269|PubMed:15294904};
CC KM=27 uM for Suc-AA-F-AMC (Membrane metallo-endopeptidase-like 1)
CC {ECO:0000269|PubMed:11964170, ECO:0000269|PubMed:15294904};
CC KM=50 uM for Suc-AA-F-AMC (Membrane metallo-endopeptidase-like 1,
CC soluble form) {ECO:0000269|PubMed:11964170,
CC ECO:0000269|PubMed:15294904};
CC KM=40 uM for Suc-AA-V-AMC (Membrane metallo-endopeptidase-like 1)
CC {ECO:0000269|PubMed:11964170, ECO:0000269|PubMed:15294904};
CC KM=100 uM for Suc-AA-V-AMC (Membrane metallo-endopeptidase-like 1,
CC soluble form) {ECO:0000269|PubMed:11964170,
CC ECO:0000269|PubMed:15294904};
CC KM=23 uM for Suc-G-LF-AMC (Membrane metallo-endopeptidase-like 1)
CC {ECO:0000269|PubMed:11964170, ECO:0000269|PubMed:15294904};
CC KM=35 uM for Suc-G-LF-AMC (Membrane metallo-endopeptidase-like 1,
CC soluble form) {ECO:0000269|PubMed:11964170,
CC ECO:0000269|PubMed:15294904};
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type II membrane protein.
CC Secreted. Note=A secreted form produced by proteolytic cleavage also
CC exists. {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P0C1T0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P0C1T0-2; Sequence=VSP_020292;
CC Name=3;
CC IsoId=P0C1T0-3; Sequence=VSP_020293;
CC Name=4;
CC IsoId=P0C1T0-4; Sequence=VSP_020294;
CC -!- TISSUE SPECIFICITY: Specifically expressed in testis and central
CC nervous system (CNS) (at protein level). Restricted to developing and
CC differentiating fields of the CNS. The soluble form is expressed in
CC round spermatides. {ECO:0000269|PubMed:10814502,
CC ECO:0000269|PubMed:12710972}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:11964170}.
CC -!- SIMILARITY: Belongs to the peptidase M13 family. {ECO:0000255|PROSITE-
CC ProRule:PRU01233, ECO:0000305}.
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DR EMBL; AABR03040205; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR AlphaFoldDB; P0C1T0; -.
DR SMR; P0C1T0; -.
DR STRING; 10116.ENSRNOP00000017957; -.
DR MEROPS; M13.008; -.
DR GlyGen; P0C1T0; 8 sites.
DR PaxDb; P0C1T0; -.
DR PRIDE; P0C1T0; -.
DR RGD; 1309299; Mmel1.
DR VEuPathDB; HostDB:ENSRNOG00000012593; -.
DR eggNOG; KOG3624; Eukaryota.
DR HOGENOM; CLU_006187_4_1_1; -.
DR InParanoid; P0C1T0; -.
DR BRENDA; 3.4.24.B14; 5301.
DR PRO; PR:P0C1T0; -.
DR Proteomes; UP000002494; Chromosome 5.
DR Bgee; ENSRNOG00000012593; Expressed in testis and 5 other tissues.
DR ExpressionAtlas; P0C1T0; baseline and differential.
DR Genevisible; P0C1T0; RN.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:RGD.
DR GO; GO:0005615; C:extracellular space; IDA:RGD.
DR GO; GO:0005794; C:Golgi apparatus; ISO:RGD.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0004175; F:endopeptidase activity; ISO:RGD.
DR GO; GO:0004222; F:metalloendopeptidase activity; IDA:RGD.
DR GO; GO:0008270; F:zinc ion binding; IDA:RGD.
DR GO; GO:0016485; P:protein processing; IBA:GO_Central.
DR GO; GO:0006508; P:proteolysis; ISO:RGD.
DR CDD; cd08662; M13; 1.
DR Gene3D; 1.10.1380.10; -; 1.
DR Gene3D; 3.40.390.10; -; 1.
DR InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR InterPro; IPR029735; MMEL1.
DR InterPro; IPR000718; Peptidase_M13.
DR InterPro; IPR018497; Peptidase_M13_C.
DR InterPro; IPR042089; Peptidase_M13_dom_2.
DR InterPro; IPR008753; Peptidase_M13_N.
DR PANTHER; PTHR11733; PTHR11733; 1.
DR PANTHER; PTHR11733:SF141; PTHR11733:SF141; 1.
DR Pfam; PF01431; Peptidase_M13; 1.
DR Pfam; PF05649; Peptidase_M13_N; 1.
DR PRINTS; PR00786; NEPRILYSIN.
DR PROSITE; PS51885; NEPRILYSIN; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Coiled coil; Disulfide bond; Glycoprotein; Hydrolase;
KW Membrane; Metal-binding; Metalloprotease; Protease; Reference proteome;
KW Secreted; Signal-anchor; Transmembrane; Transmembrane helix; Zinc.
FT CHAIN 1..774
FT /note="Membrane metallo-endopeptidase-like 1"
FT /id="PRO_0000248419"
FT CHAIN 73..774
FT /note="Membrane metallo-endopeptidase-like 1, soluble form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000248420"
FT TOPO_DOM 1..26
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 27..47
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 48..774
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT DOMAIN 84..774
FT /note="Peptidase M13"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT COILED 532..558
FT /evidence="ECO:0000255"
FT MOTIF 14..21
FT /note="Stop-transfer sequence"
FT /evidence="ECO:0000255"
FT ACT_SITE 609
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT ACT_SITE 675
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT BINDING 131
FT /ligand="a peptide"
FT /ligand_id="ChEBI:CHEBI:60466"
FT /ligand_note="substrate"
FT /evidence="ECO:0000305"
FT BINDING 608
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 612
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 671
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT SITE 72..73
FT /note="Cleavage"
FT /evidence="ECO:0000250"
FT CARBOHYD 173
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 203
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 239
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 312
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 345
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 633
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 652
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 703
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 85..90
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 108..759
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 116..719
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 171..434
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 645..771
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT VAR_SEQ 51..73
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10814502"
FT /id="VSP_020292"
FT VAR_SEQ 246..267
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:10814502"
FT /id="VSP_020293"
FT VAR_SEQ 303..313
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000305"
FT /id="VSP_020294"
FT MUTAGEN 131
FT /note="R->M: Impairs binding of free carboxylate group of
FT substrates."
FT /evidence="ECO:0000269|PubMed:15294904"
FT MUTAGEN 133
FT /note="S->G: Impairs both substrate-binding and enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:15294904"
FT MUTAGEN 567
FT /note="N->G: Impairs the enzyme specificity."
FT /evidence="ECO:0000269|PubMed:15294904"
FT MUTAGEN 739
FT /note="L->G: Impairs both substrate-binding and enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:15294904"
FT MUTAGEN 751
FT /note="P->A: Loss of function."
FT /evidence="ECO:0000269|PubMed:16081046"
FT MUTAGEN 764
FT /note="P->Y: Induces a 3-fold decrease of specific
FT activity."
FT /evidence="ECO:0000269|PubMed:16081046"
FT MUTAGEN 774
FT /note="W->F: No effect."
FT /evidence="ECO:0000269|PubMed:16081046"
SQ SEQUENCE 774 AA; 89197 MW; F95E2088CA4B64AD CRC64;
MGKSESSVGM MERADNCGRR RLGFVECGLL VLLTLLLMGA IVTLGVFYSI GKQLPLLNSL
LHVSRHERTV VKRVLRDSSQ KSDICTTPSC VIAAARILQN MDQSKKPCDN FYQYACGGWL
RHHVIPETNS RYSVFDILRD ELEVILKGVL EDSSVQHRPA VEKAKTLYRS CMNQSVIEKR
DSEPLLNVLD MIGGWPVAMD KWNETMGPKW ELERQLAVLN SQFNRRVLID LFIWNDDQNS
SRHVIYIDQP TLGMPSREYY FKEDSHRVRE AYLQFMTSVA TMLRRDLNLP GETDLVQEEM
AQVLHLETHL ANATVPQEKR HDVTALYHRM GLEELQERFG LKGFNWTLFI QNVLSSVQVE
LLPNEEVVVY GIPYLENLEE IIDVFPAQTL QNYLVWRLVL DRIGSLSQRF KEARVDYRKA
LYGTTMEEVR WRECVSYVNS NMESAVGSLY IKRAFSKDSK SIVSELIEKI RSVFVDNLDE
LNWMDEESKK KAQEKALNIR EQIGYPDYIL EDNNRHLDEE YSSLTFSEDL YFENGLQNLK
NNAQRSLKKL REKVDQNLWI IGAAVVNAFY SPNRNLIVFP AGILQPPFFS KDQPQALNFG
GIGMVIGHEI THGFDDNGRN FDKNGNMLDW WSNFSARHFR QQSQCMIYQY SNFSWELADN
QNVNGFSTLG ENIADNGGVR QAYKAYLQWL AEGGRDQRLP GLNLTYAQLF FINYAQVWCG
SYRPEFAIQS IKTDVHSPLN AQVLGSLQNL PGFSEAFHCP RGSPMHPMNR CRIW
